There is considerable evidence supporting a causal role for T-lymphocytes, monocytes, and monocytederived[unreadable] macrophages in the initiation, progression, and complications of the atherosclerosis in man as[unreadable] well as in experimental models. Plaque rupture is thought to be the trigger event for acute coronary[unreadable] syndromes in man, and several mouse models of plaque rupture have recently been described. Lesion[unreadable] macrophages in particular have been implicated in plaque rupture by releasing de-stabilizing proteases.[unreadable] Notably, there is evidence for continued recruitment of circulating monocytes into arterial lesions in[unreadable] experimental atherosclerosis, particularly in the rupture-prone shoulder. Moreover, adhesion receptors[unreadable] may also regulate critical functions of emigrated leukocytes resident in lesions, including activation and[unreadable] survival. Thus, the adhesion molecules that mediate monocyte trafficking into the arterial wall a potentially[unreadable] attractive target in advanced as well as early disease.Studies to date of human and experimental lesions[unreadable] suggest a significant role for endothelial VCAM-1 and its major leukocyte counter-receptor VLA-4 (cc4(31)[unreadable] in the early phase of disease, but have not examined the role of VLA-4 or VCAM-1 in the progression of[unreadable] established atherosclerosis or its late complications such as plaque rupture. Since antagonists of VLA-4[unreadable] have already progressed to clinical trials in other indications, the importance of VLA-4 and VCAM-1[unreadable] interactions in the progression and late complications of atherosclerosis is a clinically relevant question as[unreadable] patients are most often identified in this stage of the disease.[unreadable] We hypothesize that the VLA-4 and VCAM-1 play important roles in monocyte and T-lymphocyte[unreadable] recruitment to advanced as well as early lesions and that disruption of these adhesion pathways will[unreadable] reduce progression of established lesions and prevent plaque rupture. In order to test this hypothesis, we[unreadable] will utilize a recently developed mouse model in which interferon-induced Cre-loxP-mediated deletion of[unreadable] the ot4 gene can be achieved at any time post-natal. These a4-deleted animals will be studied in both the[unreadable] ApoE-/- (Aim 1) and LDRL-/- (Aim 2) background, allowing us to define for the first time the contribution of[unreadable] VLA-4 in the progression of established lesions and plaque rupture as well as in lesion initiation. To[unreadable] complement the VLA-4 studies, we will also examine the role of VCAM-1 in lesion initiation/progression in[unreadable] a model of conditional knockout of endothelial VCAM-1 (Aim 3).